Share

Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

"Me Too" Drugs

Bad Luck For Novartis – And For Diabetics

Novartis must wonder what they did to deserve this one. A few years ago, it looked as if they ruled the potentially lucrative world of dipeptidylylpeptidase-IV (DPP-IV) inhibitors for diabetes. (Note – name of enzyme corrected after brain hiccup – DBL). Novartis seemed to be the first big company to come up with good chemical matter in the area, and they published a whole string of papers while their lead compound went through the clinic.
Then came trouble. Merck turned out to have a big program of their own in the area, which in Merckian fashion they’d kept very quiet about, and they actually beat Novartis to the FDA. And then they beat them to market, because the agency had some questions about the Novartis compound. Those questions have done nothing but multiply. Now the problem appears to be liver tox, one of the last things the diabetic population needs. It’s looking very likely that Novartis’s compound may never get to the market in the US at all.
So here’s a question: if both compounds had made it to market, wouldn’t the people who tally up lists of “me-too” drugs have considered the first compound (from Merck) to be the original, and the Novartis one to be the copycat? After all, they target the same enzyme for the same disease in the same way. (I should mention that a DPP-IV inhibitor itself is just the sort of thing the industry is supposed to be turning out, a completely new way to treat a major and growing public health problem, but we’ll pass over that for now).
But these compounds were developed more or less simultaneously, with the two companies racing each other to the market. It’s not like either company sat back and watched the big profits roll in, and said “I need to latch on to some of that – let’s make one of those, too.” The whole thing was done on a risk basis, because while the biochemical rationale behind DPP-IV inhibition makes sense, a lot of things make sense and still go nowhere. No one really knew how the drugs would perform, either in the clinic or in the marketplace.
And take a look at the problems that the Novartis compound has. Like so many other toxicology hits, these came out of the cloudless sky. Well, actually, it’s more accurate to say that the sky over the toxicologists is never cloudless, because you never know what’s going to happen. In this case, Novartis has taken an especially painful and expensive beating, since the drug had advanced so far before the problems began to make themselves clear.
I’d like to ask some of the critics of the industry what they think about this situation. Me-too drugs are a particular arguing point with many of these people, so here we go: does that term apply in this case? If not, then why not? Should companies go after the same target in the same way at the same time? If not, then why not? How do we deal with the fact that any compound can fail at any time, other than turning companies loose to compete with each other and take as many shots at a target as possible? Do you have a better solution – and if not, well, then, why not?

34 comments on “Bad Luck For Novartis – And For Diabetics”

Seems like diprolylpeptidase-IV is an ultra googlewhack (only your site pops up).
I’m not familiar with the class of inhibitors, but a little wikipedia-ing found Dipeptidyl peptidase-4, which might be the better known alias.

Seems like diprolylpeptidase-IV is an ultra googlewhack (only your site pops up).
I’m not familiar with the class of inhibitors, but a little wikipedia-ing found Dipeptidyl peptidase-4, which might be the better known alias.

Me-too is least of concern. The lack of research productivity due to the moronic management methods, focus on quarterly reports rather than on the long term productivity and rampant abuse of incentives like stock options is what’s hurting the industry and patients alike. Something is very wrong with a discovery-based industry that’s spending more on the TV ads and the doctor bribes than on the actual research.
The industry is awfully overregulated in many aspects but it operates like gold-rush Wild West in many others. Right now it is too easy for the top management and the VCs to manipulate the system. There is huge amount of waste and dishonesty going on at every step of the process.

Mr Milkshake-
Having worked in both drug discovery and pharma sales/marketing, I must take issue with your comments regarding dishonesty and problems withing big pharma.
Your comment about $ spent on Direct 2 Consumer ads is incorrect. Where this segment of advertising is increasing, it is still a very small part of the overall marketing and sales budget, and a fraction of the $ spent on R&D by big pharma companies.
Your missing a critical point – risk. There is a HUGE amount of risk in these endeavors, which is magnified by the erratic and sometimes nonsensical behavior of the FDAgency. Our business environment is changing as rapidly as the science. It takes some very smart researchers + unlimited $$ + perfect registration trials to have a chance of approval in the US.
In short, it’s a risky, unpredictable, and many times unfair business. BUT, it’s the best we currently have. I challenge you to name a great Canadian pharma company and/or offer constuctive criticism.
~Jon in MI

The numbers are usually muddled together so that it is not obvious how much goes for what but the marketing part is tremendous. Not mentioning that all kinds of dubious-value studies are solicited and paid to lend a support to a specific claim. Whole new diseases are recognized as the unmet need – such as chronic shyness, restless legs or low libido in women. This is billed under research.
The effect of skewed rewarding schemes for top eshelons on their dishonesty is a fact. The investors are bullshited every time, tremendous value gets ruined in mergers and acqusitions – the end result is less than the sum of its parts.
The commie apparatchiks used to tell us we are alowed to make only a constructive criticism. There is plenty of decent companies in UK, France and Germany, socialzed healthcare notwithstanding.
The unpredictability of rerearch and FDA being incosistant is all true but the real expense is caused by clever management boys who milk the system while running the research to the ground

The “me-too” critique is pretty much ignorable because of the inconsistency of the critics. First they complain about pharma patent monopolies and consequent high prices, to which “me-too” drugs are the solution. Then they complain about duplicative “me-too” research, to which pharma patent monopolies are the solution.
Furthermore, besides the ex ante risk issues Derek mentioned, there may be different activities and side effects in sub-populations for the supposedly “me-too” drugs that do make it to market. Personally, I’d rather have more than one NSAID (which have not been generic since time immemorial), more than one beta blocker, etc.
Finally, can we please stop rehashing the fallacy about marketing budgets competing with R&D spending? The only way that could happen is if the marketing fails–if pharma marketing and sales groups are really out there generating sales in excess of marketing expenditures, then there is more money available for dividends, R&D, thicker carpets in the greedy executives’ offices, and everything else. Yet somehow I’ve never heard industry critics complain about advertising and sales expenditures being ineffective–they usually accuse the pharmas of bending people’s minds.

Marketing people generate sales now but the research that is in early stages will maybe in 10 years horizon. So if you are top exec paid in stock options to raise the stock price, will you put your resources into new research – or will you rather try to market the hell out of your current moneymaker?
Besides it is quite hard to find out how much a particular TV add campain contributed to the sales, especially if a competitor advrtises his product so you have to keep at it too. The direct marketing to doctors is a lot easier to track because it generates prescription – but then again the amount of freebees and other promo stuff that goes to the doctors is staggering (my ex is a pediatrician so I know it first hand)
When Hoechst was buying Marion Merrel Dow, the money they paid was not for the Marions drugs or research pipeline or management skills (they were all horrible) but for the sales network in US, for their contacts to physicians and especially for the people channels to FDA.

Bryan: DPP-IV is a dipeptidyl peptidase that cleaves more or less specifically at proline residues – it cleaves off the last 2 amino acids from the N-terminus – Derek just mashed the prolyl part into the name.
Derek: No one in the industry would call it a “me too” drug. Given the amount of time it takes to go from the lab deep into the clinic (~3-4 yrs), these two drugs would have to be discovered simultaneously (as you said). Now if 3-4 years go by and another DPP-IV inhibitor comes out, that’d be the “me too”.

Derek, you raise an excellent point about the unfair criticisms our industry receives and I 100% agree.
I am of the opinion that “me-toos” are good for the patient population, and any efforts to restrict the number of drugs in a given class (e.g., by requirements of greater efficacy that other marketed drugs in order to receive approval) would artificially create monopolies that would be bad for patients and increase the risk and cost of drug development to an unacceptable degree.
Another related mixed message given to us by our critics is the dual desire for truly new and groundbreaking therapies and cheap drugs. A great example of this was seen recently for Merck’s new drug Isentris, a first-in-class HIV integrase inhibitor. This drug is a great accomplishment, and my hat is off to Merck for it. I have been reading about the promising posibility of this type of drug for years, and I know that the HIV community has been waiting very impatiently for it (I found reference to integrase inhibitors in popular novels dating back to 2002!). However, none of this stoped HIV activists from raising a big stink when Merck suggested that they would price Isentris at similar levels to existing protease inhibitors. It’s not enough to come up with breakthroughs–we have to give them away for free, too.
Clearly, we really need to do better PR to keep the public (and their governments) focused on our real contributions to society…and real areas of weakness, too. Your blog is a good step in this direction of sanity.

“Something is very wrong with a discovery-based industry that’s spending more on the TV ads and the doctor bribes than on the actual research.”
I wish the bottom-of-the-barrel execs, like Kindler, would read this. Not that he’d actually be able to COMPREHEND anything said by “little people” outside his golf circle….
Integrase: Merck indeed deserves kudos– they’d probably been in integrase 15 years before generating a product.

It seems to me that one cannot call this a case of “me too” since these were drugs that were developed in parallel. It’s not as if there was something on the market one can reverse engineer.
The thing that confuses me is if:
“hey target the same enzyme for the same disease in the same way. ”
Then why is one stumbling over side affects and the other has passed through FDA easily?

How similar chemically are these?
Clearly these aren’t ‘me to’, but I have wondered also how careful the critics of ‘me to’ about distinguishing parallel programs from clear ‘jump in after success is shown’ ones

I just hope “Milkshake” (or a close family member) doesn’t develop a disease that will require a new innovative drug that one of the US manufacturer’s develops. If you do, you’ll be grateful for the work these companies do and the expenses they put forth to do it and maybe realize it isn’t all “fluff”.

Nobody is adressing the “Tox” issue, so I will take a stab at it ………..
The purpose of ADMET groups in Big Pharma was to be able to screen out “problem compounds” very early in Discovery.
Having worked on developing several of these In Vitro screens utilizing Human liver cell lines (at the “Wonder Factory”), I find it hard to believe that these were not picked up early on. Retrospectively, I know that the “glitazones” (ie… Troglitazone) could have been picked up with simple modern screening techniques.
I can’t wait to get my hands on these compounds to see if I could have predicted their toxicity.

Kelly- the side effects are probably caused by off-target interactions, i.e., the drug causing changes in the activity of an enzyme other than the one against which it is targeted. Since the Merck and Novartis compounds are different chemicals, they will have different off target effects. It sounds like Novartis got unlucky and their drug is hitting a liver enzyme that the Merck drug is not hitting.

NVTS vs. MRK
I think it is a bit more than luck that the MRK drug is cleaner at this point. Not only are they different molecules, but they work in different ways, do they not? The MRK drug is a pure non-covalent inhibitor, while the NVTS drug is a reversible covalent inhibitor. I’m not a big fan of generalizations, but this is one I do like: avoid covalent bonds with proteins, even reversible ones, if you can. Selectivity is harder to define, let alone measure, with covalent inhibitors.
But hey, it took guts to take an adamantane-based amidonitrile forward. Just didn’t pay off as desired.

Jon- If you think that marketing is generating the plethora of compounds that are being produced (sarcasm), then I think there maybe some drug-drug interactions going on of which you are unaware.
I don’t think MS is objecting to pharma companies or their profits, just their emphasis on marketing, outsourcing, and stock price over their stated mission and the research and development required to implement that mission.
If marketing isn’t competing for funds with R+D, but increasing the total funds available for research, increases in marketing funds might improve productivity. The emphasis on marketing, however, mandates research into areas that fit a marketing need rather than a medical lead, and leads companies to overstate the utility of a drug in order to gain market share and manufacture a blockbuster, leading to lawsuits and the likelihood that the drug won’t be used for the set of people who could use it safely.
The previous Ro5 discussion hints at the preference for some managers to have a hard and fast rule for drug development (even if it is wrong or not as general as they would like it to be), for CYA and simplicity reasons – but this would seem to be counterproductive considering the complexity of the biological systems and the limited understanding people have of them. This would not seem to enhance pharmaceutical productivity, yet it does seem to have become more prevalent lately, with the current state perhaps being a consequence.
Since we don’t understand why things work the way they do (Lipitor vs. Zocor, for example), the complaint about me-toos for real diseases seems bogus. People 1) want something for nothing and 2) are probably frustrated that the costs of medical care and drugs have increased as they have become less available, and me-toos for restless leg syndrome are as good a place as any to vent their frustration.

AJA,
First, I’m not familiar with any of the data on these compounds, but let me put in my $0.02 regarding your comment.
I’m sure that you can look back retrospectively and see the warning signs for the tox issues that Novartis now has. That, however, does not mean they should have stopped it way back when. Once again, I wasn’t there, but I think we’ve all seen projects with conflicting data that make one pause, but if there’s enough positive data to counteract the negative data, it keeps going. I’m also pretty sure that each of us can name examples of “That should have been killed a long time ago.” and “They shouldn’t have killed that one.”
I guess what I’m saying is that I have no doubt that you are correct in assuming that there is some ADME/Tox data that could have predicted these problems. But that in the absence of the totality of the data, it’s hard to say that bad decisions were necessarily made.

I interpreted Jon’s comment at milkshake more about not belittling conditions such as RLS or “chronic shyness”. I believe his point is that while many of us may not consider them “real” conditions that deserve R&D resources, people who are afflicted with these conditions truly have compromised quality of life. I don’t think he meant anything more than that.

One area that none of the comments seems to address is that DPP-IV is an enzyme with over 100 known substrates. One of those substrates is GLP-1 which appears to be the therapeutic rationale behind these compounds. There is no scientific or clinical evidence that GIP has anything to do with the benefits of these drugs.
An important question everyone should be asking is besides GLP-1 and GIP, what other substrates are being inhibited that could actually be detrimental and have not yet have fully been observed clinically? Already, there have been warnings in their prescribing information from the FDA about side effects not observed in the clinical trials such as Steven Johnson Syndrome.
So the question shouldn’t be as much about me-toos as it is about which is the safest. A chemical compound may prove clinically to offer no advantage in the general population. By the time the R&D has been done and the money spent on the animal studies and early human studies, there’s no real way to determine full differentiation until much time, money and effort has been expended.

I actually had restless legs as a kid. It was bothering me if my legs got cold, such as after skying or especially hiking when trying to fall asleep. – sleeping bag is not much confort at any settings this just made it little less so. Eventually I grew out of it.
There are unhappy shy nerdy guys (and perhaps woman without libido) – I am not just sure that overmedicating them is the best way to go about the problem. Also I had an impression that many doctors especially with HMOs turned into pill pushers and now that even goddamned psychologists prescribe antidepressants we have cases of bipolars who get misdiagnosed as “depressed’ – they get SSRIs and then turn into frank maniacs. Kids get prescribed a slow-release amphetamine to sit still in the class and so on.
I am bothered by the big pharma management. I think the drug discovery in industry has been increasingly disfunctional, the bad management is to blame for Dilbertizing or outright destroying productive research and everybody involved profits from keeping the status quo – except for the scientists and patients.
I grew under communism so I have a firsthand knowledge of socialised health care and government-directed programs. I don’t want any state bureaucrat taking care of drug discovery but there is plenty of bureaucrats and apparatchiks in industry too. I would like to see better rules for conducting the pharma business, for the top management. You know, on one hand everything related to the medical part of the industry is very regulated – but the business part of it seems like wild west goldrush environment. Since people can get incredibly rich by being a bit ishonest (many thing the IP area is very open to various interpretation and the valuation is so speculative) and since the business cycle is very slow, all kinds of business abuses go – to the point it becomes a modus operandi.
There is no good way of getting rid of dishonest top management because the personal responsibility for dumb research-affecting decisions is so easy to obscure. A rotten company evntually dies or merges but correction process takes maybe 20 years and incredible resources are wasted in the process.
We get to hear these excuses that the lack of good new drugs is caused by 1) lack of “low hanging fruit” projects 2) incresed regulatory burden 3) bad quality of university education 4) unforeseen complications – but never the more likely 5) dumb pencilpushers controlled by hochstaplers
It is amazing how the culture within a large corporation can be reminiscent of the “advanced socialism”. (In the case of Eastern Bloc the market correction took 40 years.)

I probably jumped to conclusions. Sorry.
Medications for shyness, anxiety, etc. can be useful, but the underlying conditions are likely to be multifactorial (and at least some of the factors in lots of cases aren’t necessarily going to be linked to a druggable biological system) – so medication might help but might not necessarily be the best treatment. They might help with a minimal amount of effort and resources in some cases (thus being the most effective use of resources), but in other cases the marketing might be selling their use to people that can’t be helped by them.
It seems like drug company marketing creates new diseases (when drugs are available that might treat them) the way card companies create new holidays (with the cards to give on them). The new drugs might be responses to unmet needs, but my cynicism about marketing guides me to other conclusions.

Anonymous (@20)–I agree with what you’re saying, up to a point. As a counterexample, I’d point to the ACE inhibitors. There’s an enzyme that seems to chew on anything you let it get close to, yet ACE inhibitors are some of the more benign compounds we’ve got.

The parallel time line of the development of these two drugs make it seem clear that it isn’t a me-too situation.
That said, like others who have commented here, I’ve never been completely clear on the problem with the “me-too” company strategy. Isn’t it just good competition to have more more than one company producing a compound with a common therapeutic function? Yes, the pharmaceutical industry has an important part to play in forging the path forward towards new and better drugs, but it is also in the business of doing business. If a company sees a way to improve upon a competitors product, or can legally produce a generic copy for a lower cost, that can only serve the interests of the consumer rather than confound them.
There are certainly issues with the role of the pharmaceutical industry and its relationship to health care generally, but I think these are sometimes obscured by the constant, and I think unfair, emphasis of critics on issues like marketing budgets. Of course marketing budgets will be high; a vital factor in keeping a company solvent is making sure it maintains sales of the current inventory, which in the case of the pharmaceutical industry is vital for securing funds for tomorrows inventory (not so much tomorrow’s inventory as the next decade’s inventory).
As it is, despite the $ spent on advertising, a great many academic labs are dependent on the extra money provided from industry grants directed towards basic science. Comparing R&D expenditure to marketing is a bit disingenuous. Regardless of how much is spent on marketing, a huge amount is spent on R&D also.

I saw a great talk by one of the scientists that developed the DPP-IV compound at Merck. It’s a great story in that their early compounds exhibited some nasty toxicities which was ultimately linked to inhibition of another DPP. They had some really clever tricks for finding selective compounds too.
I don’t think it ever counts as a “me too” drug until one hits the market. Good companies always have back-up compounds… you don’t call them internal “me too” candidates.

As reagrds the arguement about me-toos. It should be pointed out that Novartis were originally way ahead in this field. Their orginal development compound DPP-728 was in phase II in 1999 with a NDA slated for 2003, but this was discontinued in favour of vildagliptin.
At that time Merck was developing a low potency inhibitor licensed from ProBioDrug.
Merck made a big thing of hwo rapidly it had developed MK-431 through to phase II when it first announed the drug, as Phase III was about to commence. The novelty, as pointed out, is that this does not seek to provide a covalent bound by avoiding the typical warhead startgey used with serine protease inhibitors.

You have to understand that any scientist for any company is going to be biased towards their science and that company’s potential. It is human nature to puff out your own chest. I bet you’d hear the same thing from a Novartis scientist, an Amylin scientist and a Novo Nordisk scientist.
I am a scientist. These become labors of love. Researchers devote considerable amounts of their lives to these compounds. of course they are going to defend their compound, their backups, and the safety of them.

The DPP-IV compound is beginning to show chinks in it’s armour. SJS and anaphylaxis is just the start…Novartis had the bad luck of not making it to market, but Merck may have another Vioxx on it’s hands. Liver and renal issues are starting to emerge with Januvia…

I’m sympathetic to anyone trapped in a dysfunctional bureaucracy, and all large organizations have some of those problems. But the idea that all will be well if we just let the scientists and engineers run things without the interference of those “wild west” businessfolk is a dangerous fallacy. Veblen believed it, and so did the Technocracy movement after WWI, and so did the communists. It has never worked very well.
Honda was a brilliant inventor and engine designer, but he would have been nowhere without Fujisawa’s management acumen. Tesla was a genius, but not too successful without Westinghouse’s skill set. Henry Ford was a better engineer than Alfred Sloan, but GM kicked Ford’s butt with better marketing and organization. Managers–can’t live with ’em, can’t live without ’em.

I can live without the bad managers. I don’t want to line them all against the wall although increased accountability would be helpful.
The problem is that in pharma industry the development cycle is unusually slow and expensive and unpredictable. This causes the management to be decoupled from the consequences of their action on research so you have a perfect opportunity for all kinds of irresponsible behaviour. The stockholders can have unrealistic expectations and often the focus is very short-term. When you are a slave of quarterly reports and when the pay system for the top management is set up so that fooling the investors is rewarded and a control mechanisms are not in place, the fooling will happen – at terrible long term cost.
Most of the recent big pharma mergers should not have happened, and definitely not at the price paid. But when you pay for the acquisition of a competitor company with your own overvalued stock (that was maintained high with prevarications and cover-ups) and when you exaggerate enough the expected post-mergers synergies (“we will have 2 billions combined savings”) you will be allowed by the investors to go ahead with the merger. Then you have to make good on the “synergy” promise by firing people from the acquired company (firing your own unproductive Central Research is more dificult due to political concideration). The reckoning willeventually come – but you can allways blame it on unforeseen disasters (like the COX-2 fiasco) for it is very hard to figure out what could have been discovered and was not because you had to fire your best people 5 years ago. by the time the reckoning comes you can be a CEO of yet another company. And even in the case that you get sacked by the board you still get your retirement package 10 or 30 millions per year – every year as long as you live.

You have to understand that any scientist for any company is going to be biased towards their science and that company’s potential. It is human nature to puff out your own chest. I bet you’d hear the same thing from a Novartis scientist, an Amylin scientist and a Novo Nordisk scientist.
I am a scientist. These become labors of love. Researchers devote considerable amounts of their lives to these compounds. of course they are going to defend their compound, their backups, and the safety of them.

“You have to understand that any scientist for any company is going to be biased towards their science and that company’s potential.”
Ok, but the science was actually really cool.
I don’t know what you’re saying. If you know something I don’t, please share.

If you search online you will find many many consumers taking Januvia with terrible joint pain, which was noted in 2006 as a side effect, but not currently listed in prescribing information.
Another criminal coverup.
DPP-IV inhibition increases levels of inflammatory cytokines — people are suffering from this drug and the truth will come out eventually, but major denial is in process.